N1 modified glycopeptides

ABSTRACT

Described herein are N′-acylated derivatives of desleucylA82846B. The compounds are useful as antibacterial agents.

This application is a 371 of PCT/US99/04306, filed Feb. 26, 1999, whichclaims priority to provisional application No. 60/083,879, filed May. 1,1998.

The present invention is directed to glycopeptides and is directed inparticular to modifications of A82846B and its N^(DISACC) variations. Inthe claimed compounds, the original N¹ amino acid, N-methyl-D-leucine,has been removed and replaced with an acyl group or with an acyl groupderived from an alternate α-amino acid.

The present invention is directed to compounds of the formula

where in R¹ represents

alkanoyl of C₂-C₁₀ which is unsubstituted, or which is substituted by aphenyl, or which is substituted on other than the α-carbon atom by anamino or protected amino group;

benzoyl or substituted benzoyl bearing one or two substituents each ofwhich is independently halo, loweralkyl of C₁-C₄, loweralkoxy of C₁-C₄or phenyl;

an acyl derived from an α-amino acid or an acyl derived from a protectedα-amino acid, said α-amino acid being selected from the group consistingof:

alanine,

arginine,

asparagine,

aspartic acid,

cysteine,

glutamic acid,

glutamine,

glycine,

histidine,

isoleucine,

leucine,

lysine,

methionine,

3-phenylalanine,

3-(p-chlorophenyl) alanine,

proline,

serine,

threonine,

tryptophan and valine,

in either D- or L-form; or

an acyl derived from an α-amino acid as defined above which bears on theamine a substituent which is alkyl of C₁-C₁₀, benzyl, phenylbenzyl, orp-chlorobenzyl, with the proviso that the acyl derived fromN-methyl-D-leucine is excluded;

R² represents hydrogen, or epivancosaminyl of the formula

wherein R^(2a) represents hydrogen or —CH₂—R³; and R³ representshydrogen, alkyl of C₁-C₁₁, alkyl of C₁-C₁₁-R⁴, orR⁴-(linker_((0 or 1))-R⁴)_(o or) 1,

wherein each R⁴ is independently phenyl or phenyl substituted by one ortwo substituents, each of which is independently halo, loweralkyl ofC₁-C₈, loweralkoxy of C₁-C₈, loweralkylthio of C₁-C₄, ortrifluoromethyl, and “linker” is —O—, —CH₂—, or —O—(CH₂)_(n)— wherein nis 1-3; and the pharmaceutically acceptable salts thereof.

When R¹ represents alkanoyl of C₂-C₁₀, it can be a straight-chainalkanoyl, or it can be an alkanoyl which is branched to any degree.Likewise, when R³ represents alkyl of C₁-C₁₁, it can be straight-chainor branched.

The compounds of the present invention are prepared from thecorresponding “A82846B hexapeptides” of the formula:

wherein R² is as defined above. These “A82846B hexapeptides” are socalled because the normal N¹ amino acid N-methyl-D-leucine, has beenremoved, reducing the number of amino acids in the parent glycopeptidefrom seven to six.

The compounds of the present invention are prepared by reacting anA82846B hexapeptide with an activated ester of an alkanoic acid of thedesired acyl group R¹. By “activated ester” is meant an ester whichrenders the carboxyl function more reactive to coupling with the amineof the A82846B hexapeptide. The reaction of the A82846B hexapeptide andactivated ester is carried out in an organic solvent, suitably a polarsolvent such as dimethylformamide, dimethyl sulfoxide, or a mixture ofdimethylformamide and dimethyl sulfoxide. The reaction proceeds undertemperatures of a wide range, such as 250 to 100° C., but is preferablycarried out at temperatures of about 25 to 35° C. Some of the desiredproduct is produced shortly upon contacting the reactants, but higheryields are obtained with reaction times of from about 1 to about 24hours, oftentimes from about 1 to about 5 hours. Isolation andpurification are carried out under conventional procedures.

The starting A82846B hexapeptides are themselves synthesized from theparent glycopeptides:

wherein R^(2a) is as defined above. This synthesis is by the “Edmandegradation”, a two-step process for the cleavage of the N-terminalresidue of a peptide or protein. The above parent glycopeptide is firstreacted with an isothiocyanate of the formula SCN-R⁵, to obtain anintermediate N^(LEU) -(thiocarbamoyl)-A82846B compound of the formula

In the foregoing formula, R⁵ represents alkyl of C₁-C₁₀, phenyl,naphthyl, or phenyl substituted by one or two substituents, each ofwhich is independently halo, loweralkyl of C₁-C₄, loweralkoxy of C₁-C₄,benzyloxy, nitro, or

 wherein each R⁶ is independently loweralkyl of C₁-C₄.

This reaction is conveniently carried out in water with pyridine, at atemperature of 25°-30° C., employing a slight excess of theisothiocyanate reactant. The N^(LEU)-(thiocarbamoyl)A82846B intermediatecan be separated in conventional manner or can be employed after removalof reaction solvent in the second step of the Edman degradation.

In the second step, the N^(LEU-)(thiocarbamoyl)A82846B is reacted withan organic acid, preferably trifluoroacetic acid, in a non-polar solventsuch a dichloromethane. The reaction proceeds at temperatures of from 0°C. to 35° C. but is preferably carried out at temperatures of from 0° C.to 25° C. The reaction is generally complete in several hours. Theresulting hexapeptide product is separated and purified if desired inconventional procedures.

The second step of the Edman degradation can in some instances result inloss of the disaccharide epivancosamine. Longer reaction times can beused to obtain the desepivancosaminyl compound (R²=hydrogen).

Other variations at the disaccharide position of the molecule can beobtained in conventional procedures. As described above, the Edmandegradation and subsequent acylation can be carried out with thenaturally-occurring disaccharide (R²=epivancosaminyl with R^(2a)=H) orwith a disaccharide derivative (R²=epivancosaminyl with R^(2a)=CH₂—R³).This approach to synthesis of the present compounds is illustrated bythe preparations below of Examples 12 and 26. However, it is alsopossible to prepare those claimed compounds with a disaccharidederivative (R²=epivancosaminyl with R^(2a)=—CH₂—R³) by first conductingthe Edman degradation and subsequent acylation on A82846B, with itsnaturally occurring R²=epivancosaminyl, and thereafter introducing thedesired epivancosaminyl substituent —CH₂—R³. This is illustrated byExamples 34 and 35.

Whether the —CH₂—R³ substituent is introduced prior to Edman degradationand acylation, or after, the same conventional process is used. In thisprocess, the substrate compound is reductively alkylated with thealdehyde suitable to introduce the desired —CH₂—R³ group. This processis taught in various references, see U.S. Pat. No. 5,591,714, and EPO667,353.

The compounds of the present invention readily form salts, which can beprepared in conventional manner.

The following examples illustrate the preparation of the compounds ofthe present invention.

Preparation ofN^(LEU)-(Phenylthiocarbamoyl)-N^(DISACC)-(p-(p-chlorophenyl)benzyl)A82846B

N^(DISACC)-(p-(p-Chlorophenyl)benzyl)A82846B trihydrochloride (100.0 mg,0.0526 mmol) was dissolved in 10 ml H₂O-pyridine (1:1 v/v) and treatedwith phenyl isothiocyanate (0.010 ml, 0.083 mmol). The resulting mixturewas stirred at room temperature for 1 hr at which time HPLC analysisindicated complete consumption of the starting material. The reactionmixture was concentrated in vacuo and the crude product was purified bypreparative HPLC to give 76.6 mg (76% yield) of the title compound.FAB-MS: calc. for C₉₃H₁₀₂Cl₃N₁₁O₂₆S 1925.5, obtained 1928.5 (M+3).

Preparation of N^(DISACC)-(p-(p-Chlorophenyl)benzyl)-desleucylA82846Bfrom Isolated Thiourea

A sample of the purifiedN^(LEU)-(phenylthiocarbamoyl)-N^(DISACC)-(p-(p-chlorophenyl)benzyl)A82846B(63.3 mg, 0.0327 mmol) was suspended in 10 ml CH₂Cl₂, cooled to 0° C.,then treated with trifluoroacetic acid (0.10 ml). After 1 hr thereaction mixture was warmed to room temperature and stirred anadditional 2 hr. The solvent was removed in vacuo and the crude productwas purified by preparative HPLC to give 25.3 mg (46% yield) of thetitle compound as a white powder. FAB-MS: calc. for C₇₉H₈₄Cl₃N₉O₂₅1663.5, obtained 1666.4 (M+3).

Preparation of N^(DISACC)-(p-Phenylbenzyl)desleucylA82846B withoutIsolation of Thiourea Intermediate

N^(DISACC)-(p-Phenylbenzyl)A82846B (41.0 mg, 0.0233 mmol) was dissolvedin 4 ml H₂O-pyridine (1:1 v/v) and treated with phenyl isothiocyanate(0.0040 ml, 0.033 mmol). The resulting mixture was stirred at roomtemperature for 3 hr at which time HPLC analysis indicated completeconsumption of the starting material. The reaction mixture wasconcentrated in vacuo to give the crude thiourea intermediate as a whitesolid. The thiourea derivative was then suspended in 10 ml CH₂Cl₂,cooled to 0° C., then treated with trifluoroacetic acid (0.25 ml). After30 minutes the reaction mixture was warmed to room temperature andstirred an additional 1 hr. The solvent was removed in vacuo and thecrude product was purified by preparative HPLC to give 14.0 mg (37%yield) of the title compound as a white powder. FAB-MS: calc. forC₇₉H₈₅Cl₂N₉O₂₅ 1629.5, obtained 1632.5 (M+3).

Preparation of Example 1

A sample of desleucylA82846B (101 mg, 0.0689 mmol) and thehydroxybenzotriazole hydrate active ester of 4-phenylbenzoic acid (47mg, 0.149 mmol) was dissolved in 10 ml DMF. The resulting mixture wasstirred at room temperature for 2 hours at which time HPLC analysisrevealed complete consumption of the starting material. The reactionmixture was concentrated in vacuo and the crude product was purified bypreparative HPLC to give 14 mg (12% yield) ofN¹-(p-phenylbenzoyl)desleucylA82846B.

Preparation of Example 26

A sample of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B (140 mg, 0.0858mmol) and the hydroxybenzotriazole hydrate active ester ofN-BOC-D-proline (66 mg, 0.199 mmol) was dissolved in 12 ml DMF. Theresulting mixture was stirred at room temperature for 1 hour at whichtime HPLC analysis revealed consumption of the starting material. Thereaction mixture was concentrated in vacuo and the crude productpurified by preparative HPLC to give 77.5 mg (49% yield) ofN¹-(N-BOC-D-proline) derivative ofN^(DISACC)-(p-phenylbenzyl)desleucylA82846B.

Preparation of Example 12

A sample of purified N¹-(N-BOC-D-proline) derivative ofN^(DISACC)-(p-phenylbenzyl)desleucylA82846B (52.5 mg, 0.0287 mmol) wassuspended in 9 ml CH₂Cl₂, cooled to 0° C., then treated withtrifluoroacetic acid (0.5 ml). After 10 minutes the reaction mixture waswarmed to room temperature and stirred for an additional 50 minutes.HPLC analysis revealed complete consumption of the starting material.The solvent was removed in vacuo, and the crude product was purified bypreparative HPLC to give 15 mg (30% yield) of N¹-D-proline derivative ofN^(DISACC)-(p-phenylbenzyl)desleucylA82846B.

Preparation of Examples 34 and 35

A sample of N¹-D-leucine derivative of desleucylA82846B (95 mg, 0.0602mmol) and p-phenylbenzaldehyde (14 mg, 0.0768 mmol) was dissolved in 10ml N,N-dimethylformamide (DMF) and 10 ml methanol (MeOH). The resultingmixture was heated to 75° C. and stirred for 1 hour 15 minutes. At thistime, sodium cyanoborohydride (26 mg, 0.413 mmol) was added and thereaction stirred at 75° C. for another 1 hour 30 minutes at which timeHPLC analysis revealed consumption of the starting material. Thereaction mixture was concentrated in vacuo and the crude productpurified by preparative HPLC to give 32 mg (30%) ofN¹-(N-p-phenylbenzyl)-D-leucine derivative of desleucylA82846B and 3 mg(2.6%) of N^(DISACC)-(p-phenylbenzyl)-N¹-(N-p-phenylbenzyl)-D-leucinederivative of desleucylA82846B.

The HPLC procedures reported in these examples were as follows:

Analytical: Reactions were monitored by analytical HPLC using a WatersC18 μBondapak or Novapak C₁₈ column (3.9×300 mm) and UV detection at 280nm. Elution was accomplished with a linear gradient of 5% CH₃CN-95%buffer to 80% CH₃CN-20% buffer over 30 minutes. The buffer used was 0.5%triethylamine in water, adjusted to pH 3 with H₃PO₄.

Preparative: Crude reaction mixtures were purified by preparative HPLCusing a Waters C₁₈ Nova-Pak column (40×300 mm) and UV detection at 280nm. Elution was accomplished with a linear gradient of 5% CH₃CN-95%buffer to 80% CH₃CN-20% buffer over 30 minutes. The buffer used was 0.5%triethylamine in water, adjusted to pH 3 with H₃PO₄. The desiredfractions were subsequently desalted with a Waters C₁₈ Sep-Pak (35 cc)followed by lyophilization.

Compounds were desalted as follows. A Waters Sep-Pak cartridge waspre-wet with methanol (2-3 column volumes) then conditioned with water(2-3 column volumes). The sample, dissolved in a minimum volume ofwater, was loaded onto the Sep-Pak column which was then washed withwater (2-3 column volumes) to remove the unwanted salts. The product wasthen eluted with an appropriate solvent system, typically 1:1 CH₃CN/H₂O,CH₃CN, and/or methanol. The organic solvent component was removed invacuo and the resulting aqueous solution lyophilized to give the finalproduct.

Representative compounds of the present invention are listed in thefollowing tables:

TABLE I SIMPLE ACYL DERIVATIVES Example # FAB-MS M + X HPLC, minCompound Name 1 1644.2 1 14.7 N¹-(p-phenylbenzoyl)desleucylA82846B 21667.4 2 17.3 N¹-(8-phenyl-n-octanoyl)desleucylA82846B 3 1834.7 3 20.4N¹-(8-phenyl-n-octanoyl)-N^(DISACC)-(p-phenylbenzyl) desleucylA82846B 41564.4 3 11.0 N¹-(4-methyl-n-pentanoyl)desleucylA82846B 5 1730.4 3 17.3N¹-(4-methyl-n-pentanoyl)-N^(DISACC)-(p-phenylbenzyl) desleucylA82846B 61812.7 3 18.9 N¹-(p-phenylbenzoyl)-N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 7 1764.4 0 18.7N¹-(4-methyl-n-pentanoyl)-N^(DISACC)-[p-(p-chlorophenyl)benzyl]desleucylA82846B 8 1868.5 3 23.0N¹-(8-phenyl-n-octanoyl)-N^(DISACC)-[p-(p-chlorophenyl)benzyl]desleucylA82846B 9 1892.9 2 21.1 N¹-[7-(tert-butoxycarboxamido)-n-heptanoyl]-N^(DISACC)-[p-(p-chlorophenyl)benzyl]desleucylA82846B 10 1793.5 3 14.9N¹-(7-amino-n-heptanoyl)-N^(DISACC)-[p-(p-chlorophenyl)benzyl]desleucylA82846B

TABLE II AMINO ACID DERIVATIVES Example # FAB-MS M + X HPLC, minCompound Name 11 1845.5 3 18.3 N¹-(N-BOC-L-leucine) derivative ofN^(DISACC)-(p- phenylbenzyl)desleucylA82846B 12 1729.3 3 14.2N¹-D-proline derivative of N^(DISACC)-(p- phenylbenzyl)desleucylA82846B13 1745.4 3 14.2 N¹-D-leucine derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 14 1679.6 3 13.3 N¹-(N-BOC-D-leucine)derivative of desleucylA82846B 15 1863.3 3 18.0 N¹-(N-BOC-D-methionine)derivative of N^(DISACC)-(p- phenylbenzyl)desleucylA82846B 16 1794.7 314.9 N¹-(N,N′-DIBOC-D-lysine) derivative of desleucylA82846B 17 1579.2 38.5 N¹-D-leucine derivative of desleucylA82846B 18 1845.5 3 18.3N¹-(N-BOC-D-leucine) derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 19 1960.4 3 19.2 N¹-(N¹N′-DIBOC-D-lysine)derivative of N^(DISACC)-(p- phenylbenzyl)desleucylA82846B 20 1747.2 315.6 N¹-[N-BOC-D-3-(p-chlorophenyl)alanine] derivative ofdesleucylA82846B 21 1913.5 3 19.6 N¹-[N-BOC-D-3-(p-chlorophenyl)alanine]derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 22 1813.5 314.4 N¹-[D-3-(p-chlorophenyl)alanine] derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 23 1760.4 3 12.9 N¹-D-lysine derivative ofN^(DISACC)-(p- phenylbenzyl)desleucylA82846B 24 1663.1 3 11.6N¹-(N-BOC-D-proline) derivative of desleucylA82846B 25 1919.3 4 18.7N¹-(N-BOC-D-tryptophan) derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 26 1830.1 3 17.7 N¹-(N-BOC-D-proline)derivative of N^(DISACCC)-(p- phenylbenzyl)desleucylA82846B 27 1745.2 315.1 N¹-L-leucine derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 28 1913.4 3 19.4N¹-[N-BOC-L-3-(p-chlorophenyl)alanine] derivative ofN^(DISACC)-(p-phenylbenzyl)desleucylA82846B 29 1829.5 3 17.1N¹-(N-BOC-L-proline) derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 30 1960.5 3 19.1 N¹-(N,N′-DIBOC-L-lysine)derivative of N^(DISACC)-(p- phenylbenzyl)desleucylA82846B 31 1760.4 313.3 N¹-L-lysine derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 32 1729.4 3 14.3 N¹-L-proline derivativeof N^(DISACC)-(p- phenylbenzyl)desleucylA82846B 33 1813.3 3 16.2N¹-[L-3-(p-chlorophenyl)alanine] derivative of N^(DISACC)-(p-phenylbenzyl)desleucylA82846B 34 1745.4 3 13.3N¹-[N-(p-phenylbenzyl)-D-leucine] derivative of desleucylA82846B 351911.6 3 17.9 N¹-[N-(p-phenylbenzyl)-D-leucine] derivative ofN^(DISACC)-(p- phenylbenzyl)desleucylA82846B 36 1536.5 3 16.5N¹-(N-BOC-D-leucine) derivative of desepivancosaminyl desleucylA82846B37 1436.3 3 9.1 N¹-D-leucine derivative of desepivancosaminyl-desleucylA82846B 38 1747.4 3 14.5 N¹-(N-n-hexyl-D-leucine) derivative ofN^(DISACC)-n-hexyl desleucylA82846B 39 1661.7 1 11.0N¹-(N-n-hexyl-D-leucine) derivative of desleucylA82846B 40 1727.3 3 14.8N¹-(N-BOC-N-methyl-D-phenylalanine) derivative of desleucylA82846B 411679.2 3 14.1 N¹-(N-BOC-N-methyl-D-valine) derivative ofdesleucylA82846B 42 1577.3 1 7.7 N¹-(N-methyl-D-valine) derivative ofdesleucylA82846B

The compounds of the present invention are useful for the treatment ofbacterial infections. Therefore, in another embodiment, the presentinvention is directed to a method for controlling a bacterial infectionin a host animal, typically a warm-blooded animal, which comprisesadministering to the host animal an effective, antibacterial amount of acompound of the present invention. In this embodiment, the compounds canbe used to control and treat infections due to various bacteria, butespecially gram-positive bacteria. In a preferred embodiment, thecompounds are used to control and treat infections due to bacteriaresistant to existing antibacterials. For example, certain bacteria areresistant to methicillin, and yet others are resistant to vancomycinand/or teicoplanin. The present compounds provide a technique forcontrolling and treating infections due to such resistant bacterialspecies.

In carrying out this embodiment of the invention, the compounds of thepresent invention can be administered by any of the conventionaltechniques, including the oral route and parenteral routes such asintravenous and intramuscular. The amount of compound to be employed isnot critical and will vary depending on the particular compoundemployed, the route of administration, the severity of the infection,the interval between dosings, and other factors known to those skilledin the art. In general, a dose of from about 0.5 to about 100 mg/kg willbe effective; and in many situations, lesser doses of from about 0.5 toabout 50 mg/kg will be effective. A compound of the present inventioncan be administered in a single dose, but in the known manner ofantibacterial therapy, a compound of the present invention is typicallyadministered repeatedly over a period of time, such as a matter of daysor weeks, to ensure control of the bacterial infection.

Also in accordance with known antibacterial therapy, a compound of thepresent invention is typically formulated for convenient delivery of therequisite dose. Therefore, in another embodiment, the present inventionis directed to a pharmaceutical formulation comprising a compound of thepresent invention, in combination with a pharmaceutically-acceptablecarrier. Such carriers are well known for both oral and parenteralroutes of delivery. In general, a formulation will comprise a compoundof the present invention in a concentration of from about 0.1 to about90% by weight, and often from about 1.0 to about 3%.

The antibacterial efficacy of the present compounds is illustrated byTable III. The minimal inhibitory concentrations (MICs) were determinedusing a standard broth micro-dilution assay.

TABLE III ACTIVITY OF SIMPLE ACYL DERIVATIVES* SA Example # ResistantSensitive SA 446 SA 489 SA 447 SA X400 SA X778 SA 491 SA S13E 11991 >128 4 1 0.5 0.25 0.5 0.125 0.5 0.25 0.125 2 >128 1.5 ≦.06 ≦.06 ≦.06≦.06 ≦.06 ≦.06 ≦.06 0.125 3 6.7 2.6 1 1 1 1 1 1 2 1 4 >128 4 1 0.5 10.25 0.5 0.125 0.5 0.5 5 27 0.44 0.125 0.125 ≦.06 ≦.06 0.125 ≦.06 0.1250.25 6 38 3.5 1 2 2 1 0.5 0.5 1 0.5 7 3.4 0.22 0.5 1 0.5 0.5 1 0.125 0.51 8 4 2 16 8 8 8 4 4 8 4 9 4.8 0.66 2 1 2 2 1 1 1 1 10  5.7 0.57 ECExample # SA 1199A SH 105 SH 415 SE 270 EF 180 EF 180-1 EF 2041 EF 276EG 245 HFRD 14 1 ≦.06 2 4 0.5 64  0.125 0.125 0.125 2 no growth >64 2≦.06 1 8 0.125 8 ≦.06 ≦.06 ≦.06 0.25 no growth >64 3 0.5 1 2 1 1 ≦.060.5 0.5 2 >64 >64 4 0.5 0.25 16  0.5 >64  0.5 1 0.5 4 >64 >64 5 ≦.06≦.06 1 0.25 4 ≦.06 ≦.06 1 0.25 >64 >64 6 0.125 0.5 2 0.5 2 0.25 2 21 >64 >64 7 ≦.06 ≦.06 1 ≦.06 1 ≦.06 ≦.06 ≦.06 ≦.06  64 >64 8 2 2 8 8 2 12 1 2 >64 >64 9 0.25 0.5 1 1 2 0.5 0.5 1 1 >64 >64 10 

TABLE IV ACTIVITY OF AMINO ACID DERIVATIVES* SA Example # ResistantSensitive SA 446 SA 489 SA 447 SA X400 SA X778 SA 491 SA S13E 1199 11 451.7 1 2 1 1 0.5 2 1 1 12 2.8 0.19 2 2 0.5 1 0.25 0.5 2 1 13 2.4 0.095 10.5 1 0.5 1 1 0.5 1 14 >128 6.1 15 27 1.2 1 1 1 1 0.5 1 1 2 16 >128 717 >32 0.5 0.5 0.06 0.5 0.06 0.06 0.125 0.25 0.25 18 27 0.87 0.5 0.1250.5 0.25 0.25 ≦.06 0.5 0.5 19 64 2.6 2 1 2 2 2 1 2 2 20 >128 2 0.5 ≦.060.25 ≦.06 0.25 ≦.06 0.125 0.125 21 11 1.5 0.5 0.25 0.5 0.5 0.5 0.5 0.50.5 EC Example # SA 1199A SH 105 SH 415 SE 270 EF 180 EF 180-1 EF 2041EF 276 EG 245 HFRD 14 11 1 0.5 1 0.5 8 0.25 1 2 1 >64  >64 12 0.25 0.1250.25 0.125 1 ≦.06 0.25 1 0.25 32 >64 13 0.25 1 0.5 0.25 0.25 ≦.06 ≦.060.5 ≦.06 16 >64 14 15 0.125 1 1 0.25 8 ≦.06 0.25 0.5 1 >64  >64 16 17≦.06 0.5 1 0.25 1 ≦.06 ≦.06 0.06 0.06 32 >64 18 no growth 1 1 0.25 2 0.5≦.06 0.5 1 16 >64 19 no growth 4 4 2 8 1 0.5 2 2 >64  >64 20 no growth 816 0.125 16 0.25 ≦.06 0.125 0.5  8 >64 21 no growth 2 2 0.5 1 0.5 0.5 11  2 >64 SA Example # Resistant Sensitive SA 446 SA 489 SA 447 SA X400SA X778 SA 491 SA S13E 1199 22 6.7 0.66 1 1 1 0.5 1 0.5 2 2 23 2 0.29 10.5 1 2 2 0.5 2 0.5 24 >128 4 4 2 4 2 1 1 2 2 25 27 1.3 4 1 2 2 2 2 2 126 23 0.76 2 0.5 1 0.5 0.5 ≦.06 1 1 27 16 1 2 4 1 2 1 1 2 1 28 13 1.7 41 2 2 1 2 2 2 29 27 1.2 2 0.25 0.5 0.25 0.125 ≦.06 0.5 0.125 30 38 2.3 81 2 2 1 2 2 2 31 5.6 0.33 0.5 2 2 2 0.5 0.5 1 0.5 EC Example # SA 1199ASH 105 SH 415 SE 270 EF 180 EF 180-1 EF 2041 EF 276 EG 245 HFRD 14 220.25 2 4 0.25 2 ≦.06 1 1 0.25 >64 >64 23 0.25 1 1 0.125 0.5 ≦.06 0.50.25 0.125 >64 >64 24 1 16 32 2 >64 1 1 1 8 >64 >64 25 0.5 2 4 2 8 ≦.061 2 2 >64 >64 26 0.125 1 2 0.25 4 ≦.06 0.25 1 0.5 >64 >64 27 0.5 0.125 20.25 4 0.25 1 1 0.5  64 >64 28 1 2 4 1 2 0.5 2 1 2 >64 >64 29 ≦.06 0.1250.5 ≦.06 4 ≦.06 0.125 0.25 2 >64 >64 30 1 2 2 1 8 0.5 1 2 2 >64 >64 310.25 0.5 2 0.5 1 0.25 1 2 0.5 >64 >64 SA Example # Resistant SensitiveSA 446 SA 489 SA 447 SA X400 SA X778 SA 491 SA S13E 1199 32 16 0.76 1 11 2 0.5 0.125 0.25 0.25 33 27 2.6 1 2 1 1 1 0.5 1 0.5 34 38 0.44 0.125≦.06 0.125 ≦.06 ≦.06 ≦.06 ≦.06 0.125 35 4.8 0.66 2 2 2 2 1 1 2 2 36 >12816 8 4 16 4 4 2 4 4 37 >32 0.87 0.5 0.25 1 0.25 0.25 0.5 0.25 0.5 38 6.70.19 1 0.25 1 1 0.5 ≦.06 0.5 1 39 45 0.38 ≦.06 ≦.06 0.5 ≦.06 ≦.06 ≦.060.125 0.125 40 >128 9.2 4 4 8 4 4 2 4 4 41 >128 84 32 16 32 16 8 4 16 1642 128 0.66 0.5 0.5 0.5 0.5 2 1 1 EC Example # SA 1199A SH 105 SH 415 SE270 EF 180 EF 180-1 EF 2041 EF 276 EG 245 HFRD 14 32 ≦.06 0.125 0.50.125 2 0.125 1 2 0.5 >64 >64 33 0.25 0.5 0.5 0.25 4 0.5 2 4 1 >64 >6434 ≦.06 ≦.06 4 0.25 2 ≦.06 0.25 ≦.06 ≦.06 64 >64 35 1 0.5 2 1 1 0.25 0.51 1 >64 >64 36 4 2 >64 16 >64 4 8 4 16 >64 >64 37 0.125 0.25 4 0.5 >640.25 0.5 0.25 0.5  64 >64 38 ≦.06 1 1 1 2 no growth ≦.06 0.25 0.5 no >64growth 39 ≦.06 0.5 2 0.25 2 no growth ≦.06 ≦.06 0.5 no >64 growth 40 2 464 4 >64 4 2 1 16 >64 >64 41 8 16 64 8 >64 4 8 8 >64 no >64 growth 420.5 1 1 64 >64

*Abbreviations Organism Resistant Enterococcus faecium and faecalis(geometric mean of 4-6 isolates) Sensitive Enterococcus faecium andfaecalis (geometric mean of 4-6 isolates) SA 446 Staphylococcus aureus446 SA 489 Staphylococcus aureus 489 SA 447 Staphylococcus aureus 447 SAX400 Staphylococcus aureus X400 SA X778 Staphylococcus aureus X778 SA491 Staphylococcus aureus 491 SA S13E Staphylococcus aureus S13E SA 1199Staphylococcus aureus SA1199 SA 1199A Staphylococcus aureus SA1199A SH105 Staphylococcus haemolyticus 105 SH 415 Staphylococcus haemolyticus415 SE 270 Staphylococcus epidermidis 270 EF 180 Enterococcus faecium180 EF 180-1 Enterococcus faecium 180-1 EF 2041 Enterococcus faecalis2041 EF 276 Enterococcus faecalis 276 EG 245 Enterococcus gallinarum 245HFRD Haemophilus influenzae RD EC 14 Escherichia coli EC14

We claim:
 1. A compound of the formula

wherein R¹ represents C₂-C₁₀ alkanoyl which is substituted, or which is substituted by a phenyl group, or which is substituted at a position other than the carbon alpha- to the alkanoyl carbonyl group by an amino or protected amino group; benzoyl or substituted benzoyl bearing one or two substituents each of which is independently halo, loweralkyl of C₁-C₄, loweralkoxy of C₁-C₄ or phenyl; an α-amino acyl group wherein the α-carbon is substituted with the side chain of an amino acid in which a reactive group, when present, is optionally protected, wherein said α-amino acid is selected from the group consisting of: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, 3-phenylalanine, 3-(p-chlorophenyl)alanine, proline, serine, threonine, tryptophan and valine, in either D- or L-form; or an α-amino acyl group as defined above which bears on the amine a substituent which is alkyl of C₁-C₁₀, benzyl, phenylbenzyl, or p-chlorobenzyl, with the proviso that N-methyl-D-leucine, N-ethyl-D-leucine and derivatives thereof are excluded as an amino acids; R² represents hydrogen or an epivancosaminyl of the formula

wherein R^(2a) represents hydrogen or —CH₂—R³; and R³ represents hydrogen, C₁-C₁₁alkyl, C₁-C₁₁ alkyl-R⁴, or R⁴-(linker_(m)-R⁴)_(p), wherein m is an integer of 0 or 1; p is an integer of 0 or 1, and each R⁴ is independently phenyl or phenyl substituted by one or two substituents, each of which is independently halo, loweralkyl of C₁-C₈, loweralkoxy of C₁-C₈, loweralkylthio of C₁-C₄, or trifluoromethyl, and “linker” is —O—, —CH₂—, or —O—(CH₂)_(n)— wherein n is 1-3.
 2. A compound of claim 1 in which R² is an epivancosaminyl group wherein R^(2a) represents hydrogen.
 3. A compound of claim 2 in which R² is an epivancosaminyl group wherein R^(2a) represents —CH₂—R³.
 4. A compound of claim 3 in which R³ is p-biphenylyl.
 5. A compound of claim 3 in which R³ is p-(p-chlorophenyl)phenyl.
 6. A composition comprising a compound of claim 1 in combination with a pharmaceutically-acceptable diluent or carrier.
 7. The compound of claim 1, wherein R¹ represents C₂-C₁₀ alkanoyl which is unsubstituted, or which is substituted by a phenyl group, or which is substituted at a position other than the carbon alpha- to the alkanoyl carbonyl group by an amino or protected amino group; or benzoyl or substituted benzoyl bearing one or two substituents each of which is independently halo, loweralkyl of C₁-C₄, loweralkoxy of C₁-C₄ or phenyl.
 8. A process for the preparation of a compound as claimed in any one of claims 1-5 which comprises reacting a parent glycopeptide of the formula

wherein R² is as defined in claim 1, with an activated ester of an alkanoic acid of the desired R¹ as defined in claim 1, and optionally, thereafter reductively alkylating the N^(DISACC) amine and/or forming a pharmaceutically acceptable salt. 